Pain stickiness in pediatric complex regional pain syndrome: A role for the nucleus accumbens.

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain's responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.

Longitudinal Narrative Analysis of Parent Experiences During Graded Exposure Treatment for Children With Chronic Pain.

OBJECTIVES: Parents have a vital influence over their child's chronic pain treatment and management. Graded exposure in vivo treatment (GET) is emerging as a promising intervention for youth with chronic pain. Yet, little is known about how parents perceive GET and its impact on their child's pain condition. This study aimed to characterize caregivers' experiences over the course of their child's GET using longitudinal coding and thematic analysis of parent narratives. MATERIALS AND METHODS: Parent narratives of 15 youth who participated in GET for pediatric chronic pain (GET Living) were elicited from an unstructured dialogue at the start of each treatment session held between the parent(s) and pain psychologist. Narratives were coded for affect and content, and trends were examined in these codes across sessions. Common themes in parent narratives were developed through inductive thematic analysis. RESULTS: Parents showed an increase in positive affect, treatment confidence, and optimism over the course of treatment. Narratives also expressed more benefit-finding/growth and less anxiety and protectiveness across GET sessions, with more parents having a resolved orientation towards their child's pain by the final session. Five common themes were generated: Self-Awareness, Understanding of Their Child's Perspective, Perceived Treatment Benefit, Internalization of Treatment Principles, and Hopeful Concern for the Future. DISCUSSION: Analysis of parent narratives provides a rich and unique method for understanding a parent's journey during their child's chronic pain treatment. Clinical application of our findings can be used to guide future developments of targeted topics and interventions in the context of parenting a child with chronic pain.

Gait Variability and Relationships With Fear, Avoidance, and Pain in Adolescents With Chronic Pain.

OBJECTIVE: Some children with chronic pain struggle with fear of pain, avoidance behaviors, and associated disability; however, movement adaptations in the context of chronic pain in childhood is virtually unknown. Variability in adaptive movement responses previously observed between individuals might be largely explained by the presence of problematic psychological drivers (eg, fear, avoidance). The goals of this study were to quantify the variability of gait and examine relationships among pain, fear, avoidance, function (perceived and objective), and gait variability. METHODS: This study used a cross-sectional design. Eligible patients were between 8 and 17 years of age and had musculoskeletal, neuropathic, or headache pain that was not due to acute trauma (eg, active sprain) or any specific or systemic disease. Participants completed the Numeric Pain Rating Scale, Fear of Pain Questionnaire (FOPQ), Functional Disability Inventory, and 6-Minute Walk Test and received kinematic gait analysis. Relationships were analyzed among these measures, and the self-report and functional measures were examined to determine whether they predicted gait variability (GaitSD). RESULTS: The 16 participants who were evaluated (13.8 [SD = 2.2] years of age; 13 female) had high Numeric Pain Rating Scale scores (6.2 [SD = 2.1]), FOPQ-Fear scores (25.9 [SD = 12.1]), FOPQ-Avoidance scores (22.8 [SD = 10.2]), and Functional Disability Inventory scores (28.6 [SD = 9.4]) and low 6-Minute Walk Test distance (437.1 m [SD = 144.6]). Participants had greater GaitSD than age-predicted norms. Fear was related to self-selected GaitSD, and avoidance was related to both self-selected and standardized GaitSD. Avoidance predicted 43% and 47% of the variability in self-selected and standardized GaitSD, respectively. CONCLUSION: GaitSD was significantly related to both fear of pain and avoidance behaviors, suggesting the interplay of these psychological drivers with movement. FOPQ-Avoidance was robust in accounting for GaitSD. IMPACT: This study offers preliminary evidence in understanding movement adaptations associated with adolescents with chronic pain. They may lend to more directed interventions.

Cardiorespiratory fitness predicts effective connectivity between the hippocampus and default mode network nodes in young adults.

Rodent and human studies examining the relationship between aerobic exercise, brain structure, and brain function indicate that the hippocampus (HC), a brain region critical for episodic memory, demonstrates striking plasticity in response to exercise. Beyond the hippocampal memory system, human studies also indicate that aerobic exercise and cardiorespiratory fitness (CRF) are associated with individual differences in large-scale brain networks responsible for broad cognitive domains. Examining network activity in large-scale resting-state brain networks may provide a link connecting the observed relationships between aerobic exercise, hippocampal plasticity, and cognitive enhancement within broad cognitive domains. Previously, CRF has been associated with increased functional connectivity of the default mode network (DMN), specifically in older adults. However, how CRF relates to the magnitude and directionality of connectivity, or effective connectivity, between the HC and other DMN nodes remains unknown. We used resting-state fMRI and conditional Granger causality analysis (CGCA) to test the hypothesis that CRF positively predicts effective connectivity between the HC and other DMN nodes in healthy young adults. Twenty-six participants (ages 18-35 years) underwent a treadmill test to determine CRF by estimating its primary determinant, maximal oxygen uptake (V. O2max ), and a 10-min resting-state fMRI scan to examine DMN effective connectivity. We identified the DMN using group independent component analysis and examined effective connectivity between nodes using CGCA. Linear regression analyses demonstrated that CRF significantly predicts causal influence from the HC to the ventromedial prefrontal cortex, posterior cingulate cortex, and lateral temporal cortex and to the HC from the dorsomedial prefrontal cortex. The observed relationship between CRF and hippocampal effective connectivity provides a link between the rodent literature, which demonstrates a relationship between aerobic exercise and hippocampal plasticity, and the human literature, which demonstrates a relationship between aerobic exercise and CRF and the enhancement of broad cognitive domains including, but not limited to, memory.

Avoid or engage? Outcomes of graded exposure in youth with chronic pain using a sequential replicated single-case randomized design.

Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses; thus, targeted treatment is highly warranted. Evidence supporting graded in vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort of 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses. Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up, over 80% of participants had improved across all primary and secondary outcomes. Model-based inference analysis results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All 5 outcomes emerged as significantly improved at 3- and 6-month follow-ups. The results of this replicated single-case experimental phase design support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance.

Brain signatures of threat-safety discrimination in adolescent chronic pain.

Approximately 1.7 million youth suffer from debilitating chronic pain in the US alone, conferring risk of continued pain in adulthood. Aberrations in threat-safety (T-S) discrimination are proposed to contribute to pain chronicity in adults and youth by interacting with pain-related distress. Yet, few studies have examined the neural circuitry underlying T-S discrimination in patients with chronic pain or how T-S discrimination relates to pain-related distress. In this study, 91 adolescents (10-24 years; 78 females) including 30 chronic pain patients with high pain-related distress, 29 chronic pain patients with low pain-related distress, and 32 healthy peers without chronic pain completed a developmentally appropriate T-S learning paradigm. We measured self-reported fear, psychophysiology (skin conductance response), and functional magnetic resonance imaging responses (N = 72 after functional magnetic resonance imaging exclusions). After controlling for age and anxiety symptoms, patients with high pain-related distress showed altered self-reported fear and frontolimbic activity in response to learned threat and safety cues compared with both patients with low pain-related distress and healthy controls. Specifically, adolescent patients with high pain-related distress reported elevated fear and showed elevated limbic (hippocampus and amygdala) activation in response to a learned threat cue (CS+). In addition, they showed decreased frontal (vmPFC) activation and aberrant frontolimbic connectivity in response to a learned safety cue (CS-). Patients with low pain-related distress and healthy controls appeared strikingly similar across brain and behavior. These findings indicate that altered T-S discrimination, mediated by frontolimbic activation and connectivity, may be one mechanism maintaining pain chronicity in adolescents with high levels of pain-related distress.

Pain neuroscience education on YouTube.

OBJECTIVES: The Internet in general, and YouTube in particular, is now one of the most popular sources of health-related information. Pain neuroscience education has become a primary tool for managing persistent pain, based in part on the discovery that information about pain can change pain. Our objective was to examine the availability, characteristics, and content of YouTube videos that address the neuroscience of pain. METHODS: We conducted a systematic review of videos on YouTube using the search terms "pain education", "what is pain", and "pain brain" in January 2018. Videos were included if they were in English, were under 10 minutes long, and included information on the neuroscience of pain. Videos were coded for (i) descriptive characteristics (e.g., number of views, duration on YouTube), (ii) source and style, (iii) whether or not they addressed seven pre-determined target concepts of pain neuroscience education (e.g., 'Pain is not an accurate marker of tissue state'), and (iv) how engaging they were. RESULTS: We found 106 unique videos that met the inclusion criteria. The videos ranged from having four views to over five million views (Mdn = 1,163 views), with the three most highly viewed videos accounting for 75% of the total views. Animated videos were much more highly viewed than non-animated videos. Only a small number of videos had been posted by a clearly-identifiable reputable source such as an academic or medical institution (10%), although a number of videos were posted by healthcare professionals and professional medical societies. For a small number of videos (7%), the source was unclear. We found 17 videos that addressed at least one target concept of pain neuroscience science education, only nine of which were considered to be at least somewhat engaging. The target concept 'Pain is a brain output' was considered to be well addressed by the most videos (N = 11), followed by 'Pain is a protector' (N = 10). We found only one video that adequately addressed all seven target concepts of pain neuroscience education. DISCUSSION: YouTube contains a variety of videos that practitioners, patients, and families may view to access pain neuroscience education information. A small portion of these videos addressed one or more target concepts of pain neuroscience education in an engaging manner. It is yet to be determined to what extent patients are able to learn information from these videos, to what extent the videos promote behavior change, and thus to what extent the videos may be useful for clinical practice.

Is Empathy for Pain Unique in Its Neural Correlates? A Meta-Analysis of Neuroimaging Studies of Empathy.

Empathy is an essential component of our social lives, allowing us to understand and share other people's affective and sensory states, including pain. Evidence suggests a core neural network-including anterior insula (AI) and mid-cingulate cortex (MCC)-is involved in empathy for pain. However, a similar network is associated to empathy for non-pain affective states, raising the question whether empathy for pain is unique in its neural correlates. Furthermore, it is yet unclear whether neural correlates converge across different stimuli and paradigms that evoke pain-empathy. We performed a coordinate-based activation likelihood estimation (ALE) meta-analysis to identify neural correlates of empathy, assess commonalities and differences between empathy for pain and for non-pain negative affective states, and differences between pain-empathy evoking stimuli (i.e., facial pain expressions vs. acute pain inflictions) and paradigms (i.e., perceptual/affective vs. cognitive/evaluative paradigms). Following a systematic search, data from 128 functional brain imaging studies presenting whole-brain results of an empathy condition vs. baseline/neutral condition were extracted. Synthesizing neural correlates of empathy confirmed a core network comprising AI, MCC, postcentral gyrus, inferior parietal lobe, thalamus, amygdala, and brainstem. There was considerable overlap in networks for empathy for pain and empathy for non-pain negative affective states. Important differences also arose: empathy for pain uniquely activated bilateral mid-insula and more extensive MCC. Regarding stimuli, painful faces and acute pain inflictions both evoked the core empathy regions, although acute pain inflictions activated additional regions including medial frontal and parietal cortex. Regarding paradigms, both perceptual/affective and cognitive/evaluative paradigms recruited similar neural circuitry, although cognitive/evaluative paradigms activated more left MCC regions while perceptual/affective paradigms activated more right AI. Taken together, our findings reveal that empathy for pain and empathy for non-pain negative affective states share considerable neural correlates, particularly in core empathy regions AI and MCC. Beyond these regions, important differences emerged, limiting generalizability of findings across different affective/sensory states. Within pain-empathy studies, the core regions were recruited robustly irrespective of stimuli or instructions, allowing one to tailor designs according to specific needs to some extent, while ensuring activation of core regions.

Feeling the Pressure to Be Perfect: Effect on Pain-Related Distress and Dysfunction in Youth With Chronic Pain.

Despite clinical observation of perfectionistic tendencies among youth with chronic pain and their parents as well as established relationships between perfectionism and functional somatic symptoms in adults and youth, no research in the pediatric pain literature has examined perfectionism. This study explored the role of various types of youth and parent perfectionism on youth and parent pain-related distress and behavior and youth pain-related dysfunction. At admission, 239 parent-child pairs from outpatient and day-treatment rehabilitation settings completed several questionnaires assessing perfectionism, pain-related distress, and pain-related dysfunction. Bivariate correlations indicated that socially prescribed perfectionism in youth and parents was linked to youth pain duration, parent and youth pain-related distress and behavior, and youth somatization. Indirect relations showed that youth socially prescribed perfectionism was the only form of perfectionism directly associated with youth somatization whereas all forms of youth perfectionism were indirectly associated with somatization and functional disability through increases in youth pain-related fear and catastrophizing. Additionally, socially prescribed perfectionism was the only type of parent perfectionism linked to youth pain-related dysfunction (somatization, functional disability) through its association with youth pain-related fear. Findings support clinical observations that parent and youth perfectionism is a psychosocial factor that should be targeted in pediatric chronic pain treatment. PERSPECTIVE: Perfectionism in youth with chronic pain and their parents was indirectly linked to youth pain-related dysfunction through its effect on youth pain-related catastrophizing and fear. Findings support clinical observations that parent and youth perfectionism is a psychosocial factor that should be targeted in pediatric chronic pain treatment.